17-ether compounds of 17beta-hydroxy-5alpha-androstano[2, 3-c] furazan



United States Patent 3,332,941 17-ETHER COMPOUNDS OF IZB-HYDROXY-Sa- VANDROSTANO [2,3-c] FURAZAN Masao Shimizu, Genkichi Ohta, and KatsujiroUeno,

Tokyo, and Toshio Takegoshi, Ichikawa-shi, Japan, assignors to DaiichiSeiyaku Company Limited, Tokyo, Japan, a corporation of Japan NoDrawing. Filed Sept. 30, 1965, Ser. No. 491,863 Claims priority,application Japan, June 1, 1965, 40/ 32,369 1 Claim. (Cl. 260-23955) Thepresent invention relates to novel androstane compounds.

More particularly the present invention relates to novel steroid [2,3-c]furazan compounds in which 3- and 4- positions of a furazan ring arefused to 2- and 3-positions of the steroid nucleus possessing asubstituted-oxy group at the 17-position. These substances can berepresented by the structural formula:

wherein R represents cyclopent-l'-enyl or tetrahydropyran-2-yl group.

The compounds of the present invention,17,8-cyclopent-1-enyloxy-5a-andro-stano [2,3-c] furazan and 17;?-tetrahydropyran-2'-yloxy'5u-androstano [2,3-c] furazan were found to beexcellent orally active anabolic agents having potent myotrophic andweak androgenic activities.- The myotrophic activity was estimated bythe increase in weight of the levator ani muscle of immature castratedmale rats, and the androgenic activity by the increase in weight ofventral prostate and seminal vesicles.

Thus, in oral assay 17,8-cyclopent-1-enyloxy-5a-androstano [2,3-c]furazan showed a value of 3.3 times as myotrophic and 0.77 times asandrogenic compared with the reference standard of methyltestosterone,and 17,8- tetrahydropyran-2-yloxy 5a androstano [2,3c] furazan showed avalue of 0.95 times as myotrophic and 0.21 times as androgenic comparedwith methyltestosterone.

Anabolic hormones are useful for the treatment of cases which are causedby the poor utilization of nitrogen. Generally, however, anabolichormones are accompanied by androgenic activity and, therefore, produceundesirable side eifects. In this respect, the compounds of the presentinvention can be said to be excellent proteinanabolic agents becausethey have favorable anabolicandrogenic ratios.

The novel compounds of the present invention may be prepared byprocesses illustrated by the following equa- 3.,332w941 Patented July25, 1967 OCsHa (III) XVI) In practising the process (1) above outlined,the starting compound, 17,6 hydroxy 50c androstano [2,3-c] furazan (I)is condensed with cyclopentanone diethylacetal (II) by heating,gradually raising the temperature from 130 up to 190 C., to directlyproduce the desired l7fl-cyclopent-l-enyloxy-5a-androstano [2,3-c]furazan (IV). During the course of the reaction, it is preferable todistill off the produced low-boiling substances.

In another embodiment of the preparation process of the presentinvention, an intermediate, l7fl-(l-ethoxy) cyclopentyloxy-Sa-androstano[2,3-c] furazan (III) is prepared by heating a mixture of the compounds(I) and (II) at a temperature between and C., and then the compound(III), either isolated or not isolated, is heated, preferably in thepresence of cyclopentanone diethylacetal, gradually raising thetemperature from 130 up to C.

The process (2) above outlined is practised by condensing 178-hydroxy-5a-androstano [2,3-c] furazan (I) with 2,3-dihydropyran (V) atroom temperature in an organic solvent such as ether or benzene in thepresence of an acid such as p-toluenesulfonic acid, hydrochloric acid orsulfuric acid to produce the desiredl7B-tetrahydropyran-2-yl0xy-5a-androstano [2,3-c] furazan (VI).

ith an alkyl nitrite'in the presence of an alkali or an :id to afiord a2hydroxyimino-3-oxo-5a-androstane :rivative of the formula:

ig IQ acting the produced compound with hydroxylamine give a2,3-dihydroxyiminoandrostane compound of the rrnula:

U Hau d then heating the latter in the presence of an alkali. Thestarting compound cyclopentanone diethylacetyl I) (colorless oil, B.P.6465.5 C./19 mm. Hg) is prered by reacting cyclopentanone with ethylorthoformate Boeseken, F. Tellegen: Recueil cles travaux chimiques sPays-Bas,57,133 (1938)].

The other starting compound 2,3-dihydropyran (V) is well-known compoundalso about its preparation. l7fi-cyclopent-l-enyloxy-5m-androstano[2,3-c] fura- [1 (IV) has a colorless and needle-shaped crystal system,soluble in both benzene and ether, soluble in alcohols warm temperature,and has a melting point of 124- 6 C., [a] I +43.6 (in chloroform).17,8-tetrahydropyran2-yloxy-5ot-androstano [2,3-c] fu- :an (IV) has acolorless and needle-shaped crystal sysn, is soluble in both benzene andether, soluble in alaols at warm temperature, and has a melting point ofO1 14 C.

The following examples will illustrate the invention re fully withoutlimiting the invention thereto.

Example I A mixture of 0.32 g. of 17fl-hydroxy-5rx-androstano 3-0]furazan and 1.0 ml. of cyclopentanone diethylthe course of the reaction,the produced low-boiling substances were distilled off. The resultingproduct was dissolved in benzene and purified by passing through acolumn of alumina (8 g.). Recrystallization from a mixture of ether,methanol and a small amount of pyridine 5 afforded 0.20 g. of17fl-cyclopent-1-enyloxy-5a-androstano [2,3-c] furazan.

Elementary analysis.Calcd. for C H O N C, 75.35%; H, 8.96%; N, 7.32%.Found: C, 74.87%; H, 9.96%;N,7.11%.

10 Example 2 A mixture of 0.32 g. of 17,8-11ydroxy-5wandrostano [2,3-c]furazan and 1.0 ml. of cyclopentanone diethylacetal was heated at atemperature between 120 and 125 C. for an hour, whereby the producedlow-boiling substances were distilled off. The resulting product wasdissolved in benzene, and purified by passing through a column ofalumina (10 g). Recrystallization from a mixture of ether and ethanolafiorded 0.10 g. of 17;3-(l'-ethoxy) cyclopentyloxy 5a androstano[2,3-c] furazan having a 20 melting point of 120 122 0., +45.3 (inchloroform).

Elementary analysis.Calcd. for C H O N C, 72.86%; H, 9.41%; N, 6.54%.Found: C, 72.86%; H, 9.42%; N, 6.61%.

A mixture of 0.30 g. of thus produced 17,8-(1-eth0xy)cyclopentyloxy-5a-androstano [2,3-c] furazan and 1 ml. of cyclopentanonediethylacetal was gradually heated up to 180 C. and kept at thistemperature for 30 minutes.

Treating the resulting product in the same manner as in Example 1afforded 0.11 g. of 17/3-cyclopent 1' enyloxy-5a-androstano [2,3-c]furazan.

Example 3 To a solution of 1.42 g. of 17fi-hydroxy-5u-androstano [2,3-c]furazan in 70 ml. of ether were added 6 ml. of 2,3-dihydropyran and 260mg. of p-toluenesulfonic acid monohydrate. The mixture was allowed tostand at room temperature for an hour and a half. The reaction mixturewas washed successively with saturated aqueous sodium bicarbonate andwater, dried over anhydrous sodium sulfate and stripped of solvent atreduced pressure.

zan of the following formula:

N s o References Cited UNITED STATES PATENTS 10/1965 Cross 260-239.553/1966 Cross 260-239.55 4/1966 Ohta et al. 260239.55

LEWIS GOTTS, Primary Examiner.

E. L. ROBERTS, Examiner.

T. MESHBESHER, Assistant Examiner.

